The European Society of Cardiology (ESC) published new guidelines for the management of non–ST-elevation acute coronary syndromes (NSTE-ACS) in June 2007. This is the third edition of guidelines to be published on this topic; the first was published in 2000, and the second in 2003. Four years elapsed before this latest version was published, since there were few new developments that incited us to completely revise the NSTE-ACS guidelines. Therefore, the 2007 guidelines are not an update, but rather a whole new document, designed to take a fresh approach to the topic. The task force was composed of 11 members (10 Europeans and 1 American). The experts were selected according to their expertise in the field of cardiovascular disease, and especially acute coronary syndromes (ACS). One member of the task force was selected for his particular expertise in methodology, statistics, and meta-analysis methods.
The basic concept of the ESC panel was to provide a practical and patient-oriented document, which clinicians can use on a daily routine basis.
The task force members decided to adhere to some new basic principles in writing practice guidelines. This approach may explain why the European guidelines differ in some aspects from the American Heart Association/American College of Cardiology (AHA/ACC) American guidelines on the same topic published two months later. In particular, the European task force decided to give precedence to clinical trials that used contemporary treatments, such as pharmacologic environment including the aspirin, clopidogrel and glycoprotein (GP) IIb/IIIa inhibitors, and also revascularization strategies. Less weight was accorded to trials or meta-analyses including older studies in the field of NSTE-ACS where invasive strategy was not encouraged, or where a contemporary pharmacologic and interventional (e.g., stents) approach was not available.
Secondly, the panel took into account the methodologic quality of the clinical trials used for recommendations, giving priority to trials with adequate sample size, and disregarding trials with less robust endpoints, namely composite endpoints incorporating weak variables such as need for revascularization or other surrogate markers. Furthermore, double-blind trials were also given priority over open-label studies.
Lastly, the ESC task force particularly aimed to address some important practical issues that had never been addressed before in guidelines, such as bleeding and transfusion, and the problems posed by special populations (the elderly, females, patients with chronic kidney disease, or diabetes). In areas where evidence is lacking, it was tried to give practical recommendations such as assessment of resistance to antiplatelet therapy, association of vitamin K antagonists with dual antiplatelet therapy, etc.
Cost issues are usually not addressed in guidelines. Therefore it is a novel approach to introduce this in terms of number needed to treat (NNT) to prevent death or myocardial infarction for every treatment or procedure. This may give clinicians a clear idea of the benefit-risk ratio. Vice versa, the number needed to harm (NNH) provides a measure of the price to pay such as in terms of bleeding complications.
The present document is a summary of the official ESC guidelines, and for the purposes of conciseness, provides fewer details about the treatment effects of the different drugs and procedures proposed for the treatment of NSTE-ACS.
Cardiovascular diseases are presently the leading causes of death in industrialized countries and expected to become so in emerging countries by 2020. Among these, coronary artery disease (CAD) is the most prevalent manifestation and is associated with high mortality and morbidity. The clinical presentations of ischemic heart disease include silent ischemia, stable angina pectoris, unstable angina (UA), myocardial infarction (MI), heart failure, and sudden death. Patients with chest pain represent a very large proportion of all acute medical hospitalizations in Europe. Distinguishing those with ACS within the very large proportion with suspected cardiac pain represents a diagnostic challenge, especially in those without clear symptoms or electrocardiographic features. In spite of current treatment, the rates of death, MI, and readmission of patients with ACS remain high.
It is well established that ACS in their different clinical presentations share a widely common pathophysiologic substrate. Pathologic, angioscopic, and biological observations have demonstrated that atherosclerotic plaque rupture or erosion, with differing degrees of superimposed thrombosis and distal embolization, resulting in myocardial underperfusion, represents the basic pathophysiologic mechanisms in most ACS.
As this is a life-threatening state of atherothrombotic disease, criteria for risk stratification have been developed to allow the clinician to make timely decisions on pharmacologic management as well as on coronary revascularization strategies, tailored to the individual patient. The leading symptom that initiates the diagnostic and therapeutic cascade is chest pain, but the classification of patients is based on the electrocardiogram (ECG). Two categories of patients may be encountered: Patients with acute chest pain and persistent ST-segment elevation, and patients with acute chest pain but without persistent ST-segment elevation.
Patients with Typical Acute Chest Pain and Persistent (>20 Minutes) ST-Segment Elevation
This is termed ST-elevation ACS (STE-ACS) and generally reflects an acute total coronary occlusion. Most of these patients will ultimately develop an ST-segment elevation MI (STEMI). The therapeutic objective is to achieve rapid, complete, and sustained reperfusion by primary angioplasty or fibrinolytic therapy.
Patients with Acute Chest Pain but Without Persistent ST-Segment Elevation
Patients without persistent ST-segment elevation have instead persistent or transient ST-segment depression or T wave inversion, flat T waves, pseudo-normalization of T waves, or no ECG changes at presentation. The initial strategy in these patients is to alleviate ischemia and symptoms, to monitor the patient with serial ECG, and to repeat measurements of markers of myocardial necrosis. At presentation, the working diagnosis of NSTE-ACS, based on the measurement of troponins, will be further qualified in non–ST-segment elevation MI (NSTEMI) or UA. In a certain number of patients, coronary artery disease will subsequently be excluded as cause of symptoms. The therapeutic management is guided by the final diagnosis.
Epidemiology and Natural History
The diagnosis of NSTE-ACS is more difficult to establish than STEMI and therefore its prevalence is harder to estimate. In addition, in recent years, a new definition of MI has been introduced to take into account the use of more sensitive and more specific biomarkers of cell death. , It has been shown from surveys that the annual incidence of hospital admissions for NSTE-ACS is in the range of 3 per thousand inhabitants. This rate varies widely in Europe, with considerably higher incidence in Central and Eastern Europe as compared with Western Europe. Over time, the rate of NSTE-ACS has increased gradually, whereas the rate of STEMI has decreased. Nowadays, NSTE-ACS represents a higher proportion of hospitalizations than STEMI.
Similarly, surveys have established that the prognosis of NSTE-ACS also varies considerably. The death rate is lower during the first 30 days than for STEMI, but at 1 year, the death rate is virtually the same in both conditions.
The implications for therapy are as follows:
NSTE-ACS is more frequent than STEMI.
In contrast to STEMI, where most events occur before or shortly after presentation, in NSTE-ACS these events continue over days and weeks.
Mortality rates of STEMI and NSTE-ACS after 6 months are comparable.
This suggests that treatment strategies for NSTE-ACS need to address the requirements of the acute phase as well as longer-term treatment.
Atherosclerosis is a chronic, multifocal immuno-inflammatory, fibroproliferative disease of medium-sized and large arteries mainly driven by lipid accumulation. Symptomatic coronary lesions contain a variable mix of chronic atherosclerosis and acute thrombosis. Since the exact nature of the mix is unknown in the individual patient, the term atherothrombosis is frequently used. Generally, atherosclerosis predominates in lesions responsible for chronic stable angina, whereas thrombosis constitutes the critical component of culprit lesions responsible for the ACS. ,
ACS represent a life-threatening manifestation of atherosclerosis usually precipitated by acute thrombosis, induced by a ruptured or eroded atherosclerotic plaque, with or without concomitant vasoconstriction, causing a sudden and critical reduction in blood flow. In the complex process of plaque disruption, inflammation was revealed as a key pathophysiologic element. In rare cases, ACS may have a nonatherosclerotic etiology such as arteritis, trauma, dissection, thromboembolism, congenital anomalies, cocaine abuse, and complications of cardiac catheterization.
The Vulnerable Plaque
Atherosclerosis is not a continuous, linear process but rather a disease with alternate phases of stability and instability. Plaque rupture or plaque erosion are the two main underlying mechanisms in acute coronary syndromes. The plaques prone to instability and rupture have a large lipid core, a low density of smooth muscle cells, a high concentration of inflammatory cells, and a thin fibrous cap covering the lipid core as compared with stable plaques.
Coronary thrombosis in ACS usually develops at the site of a vulnerable ruptured or eroded plaque. The thrombus is fibrin-rich and completely occlusive in STEMI, whereas it is platelet-rich and partially or intermittently occlusive in NSTE-ACS. A platelet-rich thrombus at the site of plaque rupture may fragment into small particles, which embolize downstream and may occlude arterioles and capillaries. These platelet emboli may cause small areas of necrosis in the myocardium.
The Vulnerable Patient
Multiple sites of plaque rupture with or without intracoronary thrombosis, along with elevated levels of various systemic markers of inflammation and thrombosis as well as coagulation system activation have been documented in patients with ACS. Hypercholesterolemia, tobacco smoking, and increased fibrinogen levels have been reported to contribute to instability in these patients, leading to thrombotic complications.
Endothelial Vasodilatory Dysfunction
Minor changes in coronary tone may greatly affect myocardial blood supply and thus cause insufficient flow at rest or during exercise. Vasospasm most frequently occurs at the site of atherosclerotic plaques in which local vasoconstricting substances, such as serotonin, thromboxane A 2 , and thrombin are released locally by platelets and intracoronary thrombi. The prototype of dynamic coronary obstruction as a cause of ACS is Prinzmetal’s variant angina, in which coronary vasospasm is the main determinant of an abrupt reduction in flow. This usually occurs at sites of critical or subcritical stenoses.
A number of extracardiac mechanisms can cause a critical increase in myocardial oxygen consumption to above the supply threshold, such as fever, tachycardia, thyrotoxicosis, hyperadrenergic state, sudden emotional stress, and increased left ventricular (LV) afterload (hypertension, aortic stenosis).
The myocardium may be normal or there may be varying degrees of necrosis. Focal myocardial necrosis was shown to be surrounded by areas of inflammation. In clinical practice this minor damage may be detected only by cardiac troponin T (cTnT) or troponin I (cTnI) elevations and are classified as MI according to the ESC/AHA/ACC Consensus Document. This concept is of clinical importance, because it has major practical implications with respect to short-term prognosis and the choice of the therapeutic regimen.
Diagnosis and Risk Assessment
Diagnosis and risk stratification are closely linked in ACS. Patients with NSTE-ACS are at high risk for MI, recurrence of MI, or death. Risk must not be understood in a binary way, but rather as a continuum from patients with very high risk to patients with low risk.
Clinical Presentation and History
The clinical presentation of NSTE-ACS encompasses a wide variety of symptoms. Traditionally, several clinical presentations have been distinguished:
Prolonged (>20 minutes) anginal pain at rest.
New onset (de novo) severe angina (class III of the Classification of the Canadian Cardiovascular Society (CCS).
Recent destabilization of previously stable angina with at least CCS class III angina characteristics (crescendo angina).
Or post-MI angina.
Prolonged pain is observed in 80% of patients, while de novo or accelerated angina are observed in only 20%.
In patients with intermittent symptoms, an increasing number of episodes preceding the index event may also have an impact on outcome. The presence of tachycardia, hypotension, or heart failure upon presentation indicates a poor prognosis and needs rapid diagnosis and management. It is important to identify clinical circumstances that may exacerbate or precipitate NSTE-ACS, such as anemia, infection, inflammation, fever, and metabolic or endocrine (in particular thyroid) disorders.
The physical examination is frequently normal. Signs of heart failure or hemodynamic instability must prompt the physician to expedite the diagnosis and treatment of patients. An important goal of the physical examination is to exclude noncardiac causes of chest pain, and nonischemic cardiac disorders.
The resting 12-lead ECG is the first-line diagnostic tool in the assessment of patients with suspected NSTE-ACS. It should be obtained within 10 minutes after first medical contact upon arrival of the patient in the emergency room and immediately interpreted by a qualified physician. The findings range from normal ECG (observed in 5% of proven NSTE-ACS) to T wave inversion or ST depression. Depending on the number of leads where it is observed and its magnitude, ST depression has a strong prognostic implication. The prognostic implication of T wave inversion is less severe than for ST depression.
Continuous ST-Segment Monitoring
On-line continuous computer-assisted 12-lead ST-segment monitoring is a valuable diagnostic tool. Several studies revealed that 15% to 30% of patients with NSTE-ACS have transient episodes of ST-segment changes, predominantly ST-segment depression. ST-monitoring adds independent prognostic information to the ECG at rest, troponins, and other clinical parameters.
Exercise or Other Stress Testing
In patients who continue to have typical ischemic rest pain, no stress test should be performed. However, a stress test has a predictive value and is therefore useful before discharge in patients with non-diagnostic ECG provided there is no pain, no signs of heart failure, and normal biomarkers (repeat testing).
Several biomarkers have been investigated in recent years to be used for diagnostic and risk stratification. These reflect different pathophysiologic aspects of NSTE-ACS, such as minor myocardial cell injury, inflammation, platelet activation, or neurohormonal activation. For the long-term prognosis, indicators of LV and renal dysfunction or diabetes play also an important role.
Markers of Myocardial Injury
Troponin T (cTnT) or cTnI are the preferred markers of myocardial injury, because they are more specific and more sensitive than the traditional cardiac enzymes such as creatine kinase (CK) or its isoenzyme MB (CK-MB). They reflect irreversible myocardial cellular necrosis resulting from distal embolization of platelet-rich thrombi from the site of a ruptured or eroded plaque. Troponins are the best biomarker to predict short and long term outcome with respect to MI and death. , They are also useful for selecting appropriate treatment in patients with NSTE-ACS. An initial rise in troponins in peripheral blood occurs after 3 to 4 hours. Troponin levels may be persistently elevated for up to 2 weeks; this is caused by proteolysis of the contractile apparatus. Minor or moderate elevations of troponins appear to carry the highest early risk in patients with NSTE-ACS.
A single negative test for troponins on arrival of the patient in hospital is not sufficient for ruling out, as in many patients troponin rise can be detected only in the subsequent hours. In order to demonstrate or to exclude myocardial damage, repeated blood sampling and measurements are required 6 to 12 hours after admission and after any further episodes of severe chest pain. A second sample in the absence of any other suspicious findings may be omitted only if the patient’s last episode of chest pain was more than 12 hours prior to the initial determination of troponins. Elevation of troponins can be observed in many other clinical circumstances, but do not truly reflect myocardial infarction in the absence of clinical symptoms of ischemia and obstructive coronary artery disease. Differential diagnosis can be difficult. The conditions that are associated with troponin release have been summarized elsewhere. In brief, troponins can be elevated in the following conditions: (1) severe congestive heart failure; (2) aortic dissection; (3) cardiac contusion (ablation, pacing); (4) myocarditis, endocarditis or pericarditis; (5) hypertensive crisis; (6) tachyarrhythmias or bradyarrhythmias; (7) pulmonary embolism; (8) apical ballooning syndrome; (9) chronic or acute renal dysfunction; (10) acute neurologic disease, including stroke or subarachnoid hemorrhage; (11) drug toxicity (e.g., Adriamycin, 5-fluorouracil, Herceptin); (12) snake venoms; (13) burns if affecting more than 30% of body surface area; (14) rhabdomyolysis; and (15) critically ill patients, especially with respiratory failure, or sepsis.
This means that the diagnosis of NSTE-ACS should never be made only on the basis of cardiac biomarkers whose elevation should be interpreted in the context of other clinical findings.
Markers of Inflammatory Activity
Of the numerous inflammatory markers that have been investigated over the past decade, C-reactive protein measured by high sensitive assays (hsCRP) is the most widely studied and linked to higher rates of adverse events. There is robust evidence that even among patients with troponin-negative NSTE-ACS, elevated levels of hsCRP are predictive of long-term mortality (>6 months).
Markers of Neurohumoral Activation
Natriuretic peptides, like brain type (B-type natriuretic peptide [BNP]) or its N-terminal prohormone fragment (NT-proBNP) are highly sensitive and fairly specific markers for the detection of LV dysfunction. There is robust retrospective data in NSTE-ACS showing that patients with elevated BNP or NT-proBNP levels have a 3-fold to 5-fold increased mortality rate as compared with those having lower levels. The level is strongly associated with the risk of death even when adjusted for age, Killip class, and LV ejection fraction (LVEF). However, they are markers of long-term prognosis, but have limited value for initial risk stratification and hence for selecting the initial therapeutic strategy in NSTE-ACS.
Markers of Renal Function
Impaired renal function is a strong independent predictor for long-term mortality in ACS patients. Long-term mortality is influenced by the degree of renal function, as it increases exponentially with decreasing glomerular filtration rate/creatinine clearance (GFR/CrCl). As compared with patients with normal renal function, the odds ratio (OR) for death at 1 year was 1.76 for mild renal dysfunction, 2.72 for moderate renal dysfunction, and 6.18 for severe renal dysfunction.
Currently, it is recommended to use troponins (cTnT or cTnI) for the acute risk stratification on arrival of the patient in the hospital. At the same time or during the subsequent days CrCl and BNP or NT-proBNP allow the estimation of any renal or myocardial dysfunction with their inherent impacts on treatment and long-term outcome. Currently only hsCRP is available on a routine basis for the detection of the underlying inflammatory activity responsible for long-term mortality.
Echocardiography and Noninvasive Myocardial Imaging
Echocardiography is an important tool to quantify LV function, and rule out differential diagnoses. Other noninvasive tools can be useful for the same purposes. Aortic stenosis, aortic dissection, pulmonary embolism, or other conditions can mimic ACS and can be ruled out with echocardiography. Magnetic resonance imaging (MRI) is a valuable alternative to echocardiography.
Imaging of the Coronary Anatomy
The gold standard is still conventional invasive coronary angiography.
Patients with multiple vessel disease as well as those with left main stenosis are at highest risk of serious cardiac events. Angiographic assessment of the characteristics and location of the culprit lesion as well as other lesions is essential if revascularization is being considered. At the current state of development, cardiac computed tomography (CT) cannot be recommended as coronary imaging modality in NSTE-ACS, because of suboptimal diagnostic accuracy.
MRI is not established as an imaging tool for coronary arteries. It may only be useful in the course of hospitalization in quantifying myocardial injury or excluding myocarditis. CT or MRI may, however, be indicated for evaluation of differential diagnoses, such as pulmonary embolism or aortic dissection.
Several cardiac and noncardiac conditions may mimic NSTE-ACS. Some are cardiac, vascular, or pulmonary conditions such as myocarditis, pericarditis, myopericarditis, cardiomyopathy, apical ballooning (Tako-Tsubo syndrome), pulmonary embolism, pulmonary infarction, pneumonia, pneumothorax, aortic dissection, aortic aneurysm, and aortic coarctation. Other conditions may also mimic the clinical scene of ACS, with gastrointestinal causes including esophageal spasm, esophagitis, peptic ulcer, pancreatitis, cholecystitis, or orthopedic/traumatic causes such as cervical discopathy, rib fracture, muscle injury/inflammation, costochondritis, or even hematologic causes such as sickle cell anemia.
Several risk stratification scores have been developed and validated in large patient populations. In clinical practice only simple risk scores are useful.
The GRACE risk scores are based upon a large unselected population of an international registry of full spectrum of ACS patients. The risk factors were derived with independent predictive power for in-hospital deaths and postdischarge deaths at 6 months. Based on direct comparisons, the GRACE risk score is recommended as preferred classification to apply on admission and at discharge in daily clinical routine practice.
Other risk scores have been developed (e.g., the TIMI and PURSUIT risk scores).
Recommendations for Diagnosis and Risk Stratification
Diagnosis and short-term risk stratification of NSTE-ACS should be based on a combination of clinical history, symptoms, ECG, biomarkers and risk score results (I-B).
The evaluation of the individual risk is a dynamic process that is to be updated as the clinical situation evolves.
A 12-lead electrocardiogram (ECG) should be obtained within 10 minutes after first medical contact and immediately read by an experienced physician. (I-C) Additional leads (V 3R and V 4R , V 7 -V 9 ) should be recorded. ECG should be repeated in case of recurrence of symptoms, and at 6 hours, 24 hours, and before hospital discharge (I-C)
Blood must be drawn promptly for troponin (cTnT or cTnI) measurement. The result should be available within 60 minutes. (I-C) The test should be repeated after 6 to 12 hours if the initial test is negative (I-A)
Established risk scores (such as GRACE) should be implemented for initial and subsequent risk assessment (I-B)
An echocardiogram is recommended to rule in or out differential diagnoses (I-C)
In patients without recurrence of pain, normal ECG findings, and negative troponin tests, a noninvasive stress test for inducible ischemia is recommended before discharge (I-A)
The following predictors of long-term death or MI should be considered in risk stratification (I-B):
Clinical indicators : age, heart rate, blood pressure, Killip class, diabetes, previous MI/CAD
ECG markers: ST-segment depression
Laboratory markers: troponins, GFR/CrCl/Cystatin C, BNP/NT-proBNP, hsCRP
Imaging findings: low ejection fraction, main stem lesion, three-vessel disease.
Risk score result
The treatment options described in this section are based on evidence from numerous clinical trials or meta-analyses.
Four categories of acute treatment are discussed: anti-ischemic agents, anticoagulant, antiplatelet agents, and coronary revascularization. Generally, the therapeutic approach is based on whether the patient is to be only medically treated, or in addition referred to angiography and revascularization. Many of the treatment options were evaluated more than two decades ago or tested only in specific subsets of patients. The recommendations take these circumstances into account.
Anti-ischemic drugs decrease myocardial oxygen consumption (decreasing heart rate, lowering blood pressure, or depressing LV contractility) and/or induce vasodilatation.
A meta-analysis suggested that beta-blocker treatment was associated with a 13% relative reduction in risk of progression to STEMI. Although no significant effect on mortality in NSTE-ACS has been demonstrated in these relatively small trials, the results may be extrapolated from larger randomized trials of beta blockers in patients with unselected MI.
Studies of nitrates in unstable angina have been small and observational. In patients with NSTE-ACS who require hospital admission, intravenous nitrates may be considered in the absence of contraindications. The dose should be titrated upward until symptoms (angina and/or dyspnea) are relieved unless side effects (notably headache or hypotension) occur.
Calcium Channel Blockers
From meta-analyses, no significant effect on death and non-fatal MI has been shown with the use of calcium channel blockers. On the contrary, observational studies suggest that short-acting nifedipine might be associated with a dose-dependent detrimental effect on mortality in patients with coronary artery disease. There is evidence that diltiazem might be beneficial in NSTEMI. Calcium channel blockers, particularly dihydropyridines, are the drugs of choice in vasospastic angina.
New antianginal drugs with different modes of action have been investigated in recent years. Only ranolazine, which exerts antianginal effects by metabolic mechanisms, was tested in a large ACS trial, but was not effective in reducing major cardiovascular events.
Recommendations for Anti-Ischemic Drugs
Beta blockers are recommended in the absence of contraindications, particularly in patients with hypertension or tachycardia. (I-B)
Intravenous or oral nitrates are effective for symptom relief in the acute management of anginal episodes. (I-C)
Calcium channel blockers provide symptom relief in patients already receiving nitrates and beta blockers; they are useful in patients with contraindications to beta blockade, and in the subgroup of patients with vasospastic angina. (I-B)
Nifedipine, or other dihydropyridines, should not be used unless combined with beta blockers. (III-B)
Anticoagulants are used in the treatment of NSTE-ACS to inhibit thrombin generation, thombin activity, or both, thereby reducing thrombus-related events. There is clear evidence that anticoagulation is effective in addition to platelet inhibition and that the combination of the two is more effective than either treatment alone. With all anticoagulants, there is an increased risk of bleeding. The risk factors for bleeding are well defined. Several anticoagulants, which act at different levels of the coagulation cascade, have been investigated in NSTE-ACS:
Unfractionated heparin (UFH) as intravenous infusion
Low–molecular-weight heparin (LMWH) as subcutaneous injection
Fondaparinux as subcutaneous injection every 24 hours
Direct thrombin inhibitors (DTI) as intravenous infusion
Vitamin-K antagonists (VKA) as oral medication
A pooled analysis of six trials testing short-term UFH versus placebo or untreated controls showed a significant 33% risk reduction for death and MI (OR, 0.67; 95% confidence interval [CI], 0.45-0.99; P = .045). The risk reduction for MI accounted for practically all of the beneficial effect. When the data from FRISC, which compared LMWH to placebo, are added to this pooled analysis, then the risk reduction is even greater. In trials comparing the combination of UFH plus aspirin versus aspirin alone in NSTE-ACS, a trend toward a benefit was observed in favor of the UFH-aspirin combination, but at the cost of an increase in the risk of bleeding. Recurrence of events after interruption of UFH explains why this benefit is not maintained over time, unless the patient is revascularized before the interruption of UFH. ,
Low–Molecular-Weight Heparin (LMWH) ,
Several LMWHs are available for the treatment of patients with NSTE-ACS. Dalteparin and nadroparin were shown to be equally efficacious and safe as UFH in aspirin-treated patients. Enoxaparin has been compared with UFH in several trials. A meta-analysis of these trials totaling 21,946 patients showed no significant difference between the two compounds for death at 30 days, but a significant reduction in the combined endpoint of death and MI in favor of enoxaparin versus UFH (10.1% vs. 11.0%; OR, 0.91; 95% CI, 0.83-0.99). In this analysis, no significant difference was observed in the rate of bleeding or blood transfusion. The SYNERGY study was the most recent trial to compare enoxaparin to UFH. It incorporated 10,027 high-risk patients planned for early invasive evaluation and revascularization. This trial used contemporary treatment, with extensive use of stents, GP IIb/IIIa inhibitors, and clopidogrel. Almost half of the patients included in the trial were submitted to percutaneous coronary intervention (PCI) or other forms of revascularization. No significant difference was observed in terms of death and MI at 30 days, but an excess of bleeding occurred with enoxaparin, with a statistically significant increase in TIMI major bleeding (9.1% vs. 7.6%, P = .08), but a nonsignificant excess in GUSTO severe bleeding and transfusion.
LMWH, particularly enoxaparin, was used in combination with aspirin and thienopyridines, as well as GP IIb/IIIa inhibitors without safety concerns.
Factor-Xa Inhibitor (Fondaparinux)
The only selective factor-Xa inhibitor available for clinical use is fondaparinux. This is a synthetic pentasaccharide that exerts a selective antithrombin mediated inhibition of factor-Xa, resulting in a dose-dependent inhibition of thrombin generation without inhibition of the thrombin molecule per se.
Fondaparinux was compared to enoxaparin in a large trial incorporating 20,078 patients with NSTE-ACS, namely the OASIS-5 study. Fondaparinux was used at a dose of 2.5 mg subcutaneous once daily, versus subcutaneous enoxaparin 1 mg/kg twice daily for 8 days maximum. At 9 days, there was no significant difference in the rate of primary endpoint (death, MI, or refractory ischemia) but there was a significant, 48% reduction of major bleeding. At 1 month, there was a significant reduction in death, which was sustained at 12 months. It was shown from further analysis that most of the beneficial effect observed in the risk reduction for death was linked to the reduction in bleeding. An excess of catheter thrombus during PCI was observed in the fondaparinux group as compared with the enoxaparin group (0.9% vs. 0.4%, P = .001). However, catheter thrombus was abolished over the duration of the trial by using a single bolus of UFH, added to fondaparinux in patients submitted to PCI without increasing bleeding risk.
Direct Thrombin Inhibitors (DTI)
Direct thrombin inhibitors bind directly to thrombin (factor IIa) and thereby inhibit thrombin-induced conversion of fibrinogen into fibrin. No significant beneficial effects were observed, but a higher bleeding rate was elicited from meta-analysis of the early trials carried out with direct thrombin inhibitors. The most recent trial, ACUITY, used bivalirudin and randomized 13,819 patients with moderate to high risk NSTE-ACS planned for invasive strategy to three arms in an open-label design (conventional anticoagulant plus GP IIb/IIIa inhibitors, bivalirudin plus GP IIb/IIIa inhibitors, bivalirudin alone). The primary endpoint was composite of ischemic events and bleeding complications. There was no significant difference, either in terms of efficacy or safety, between conventional anticoagulants plus GP IIb/IIIa inhibitors, and bivalirudin plus GP IIb/IIIa inhibitors. There was a significant risk reduction for bleeding with bivalirudin alone compared with a combination of conventional anticoagulants plus GP IIb/IIIa inhibitors, at the cost of a nonsignificant excess of ischemic events. The risk reduction of bleeding in ACUITY did not translate into a risk reduction for death at 30 days and 6 months. The treatment effects were consistent in all subgroups, except in patients who were not pretreated with clopidogrel before being submitted to PCI. Some criticisms have been leveled at this study since its publication because of a rather liberal margin of noninferiority used in the design of the trial.
Vitamin-K Antagonists (VKA)
In the current era of combining aspirin with clopidogrel in NSTE-ACS, VKA are mostly used in the presence of other indications for anticoagulation, such as atrial fibrillation or after implantation of a mechanical heart valve.
Based on experiences from clinical practice, it seems that antiplatelet and VKA combinations lead to only modest increases in bleeding risk in elderly patients, provided tight control of international normalized ratio (INR) can be obtained. In patients with active VKA treatment presenting with ACS, initiation of the anticoagulants recommended during the acute phase (UFH, LMWH, fondaparinux, or bivalirudin) should be withheld as long as the INR is not known and not started before the INR is less than 2.0. Reversal of anticoagulation with vitamin K supplements is not recommended unless necessary for bleeding complications.
Anticoagulants During Percutaneous Coronary Intervention Procedures in Non–ST-Segment Elevation Acute Coronary Sydrome
The use of platelet inhibition with aspirin and systemic anticoagulation with UFH has been the standard of care for PCI from the beginning. The current recommendation, based on empiric evidence, is to give UFH as an intravenous bolus of 100 IU/kg or 50 to 60 IU/kg if GP IIb/IIIa inhibitors are given. The efficacy of UFH is monitored by activated clotting time (ACT). However, the relation between ACT and the rate of clinical events, and the real utility of ACT monitoring remains controversial.
Bivalirudin during PCI procedures was tested in comparison to UFH/LMWH or bivalirudin plus GP IIb/IIIa inhibitors in the ACUITY trial. As already mentioned, a significant risk reduction for bleeding was observed with bivalirudin alone as compared to UFH/LMWH or bivalirudin with GP IIb/IIIa inhibitors, but with a significantly higher rate of ischemic events in patients not pretreated with clopidogrel.
Enoxaparin (1 mg/kg twice daily) was compared to UFH as antithrombotic agent in a PCI setting in 4687 NSTE-ACS in the SYNERGY trial. There was no difference in outcome during or after PCI, regardless of the drug used in the catheterization laboratory (UFH or enoxaparin). However, there was a strong trend toward an excess of bleeding (non–coronary artery bypass grafting [CABG]-related TIMI major bleeds) with enoxaparin, as compared with UFH, possibly augmented by post-randomization crossover antithrombotic therapy. A recent trial (STEEPLE) involving 3258 patients undergoing elective PCI, suggests that lower doses of enoxaparin may be favorable with respect to bleeding.
Enoxaparin and fondaparinux were compared in the setting of PCI in 6239 patients in OASIS-5. Fondaparinux resulted in a lower risk of vascular access site complications as compared with enoxaparin and also in a lower risk of periprocedural complications (death, MI, stroke, and major bleeding). Catheter thrombus formation occurred more frequently with fondaparinux as compared with enoxaparin. Until new data are available, a standard dose of UFH (50-100 IU/kg bolus) is needed in addition to fondaparinux at the time of PCI, if fondaparinux was initiated prior to the procedure.
Recommendations for Anticoagulation
Anticoagulation is recommended for all patients in addition to antiplatelet therapy (I-A)
Anticoagulation should be selected according to the risk of both ischemic and bleeding events (I-B)
Several anticoagulants are available, namely UFH, LMWH, fondaparinux, and bivalirudin. The choice depends on the initial strategy (see section on Management Strategy : urgent invasive, early invasive, or conservative strategies) (I-B)
In an urgent invasive strategy UFH (I-C), or enoxaparin (IIa-B) or bivalirudin (I-B) should be immediately started.
In a nonurgent situation, as long as decision between early invasive or conservative strategy is pending:
Fondaparinux is recommended on the basis of the most favorable efficacy and safety profile (I-A)
Enoxaparin with a less favorable efficacy and safety profile than fondaparinux should be used only if the bleeding risk is low (IIa-B)
As the efficacy and safety profile of LMWH (other than enoxaparin) or UFH relative to fondaparinux is unknown, these anticoagulants cannot be recommended over fondaparinux (IIa-B)
At PCI procedures the initial anticoagulant should be maintained also during the procedure regardless whether this treatment is UFH (I-C), enoxaparin (IIa-B) or bivalirudin (I-B), while addititional UFH in standard dose (50-100 IU/kg bolus) is necessary in case of fondaparinux (IIa-C)
Anticoagulation can be stopped within 24 hours after invasive procedure (IIa-C). In a conservative strategy, fondaparinux, enoxaparin, or other LMWH may be maintained up to hospital discharge (I-B)
Platelet activation plays a key pathophysiologic role in NSTE-ACS. Three related, but complementary strategies provide effective antiplatelet therapy: cyclooxygenase-1 inhibition (COX-1; aspirin), inhibition of ADP-mediated platelet aggregation with thienopyridines (ticlopidine and clopidogrel), and GP IIb/IIIa inhibition (tirofiban, eptifibatide, abciximab).
Acetylsalicylic Acid (Aspirin)
In a meta-analysis, aspirin was shown to lead to a 46% reduction in the rate of vascular events in the setting of NSTE-ACS. No dose relation was observed in terms of efficacy. Doses ranging from 75 to 150 mg of aspirin were shown to be as effective as higher doses, but resulted in fewer bleeding complications.
Ticlopidine and clopidogrel are both adenosine diphosphate (ADP) receptor antagonists, which block the ADP-induced pathway of platelet activation by specific inhibition of the purinergic G protein–coupled P2Y 12 (P2Y12) ADP receptor. Ticlopidine has been shown to significantly reduce the risk of death and MI at 6 months in NSTE-ACS. However, clopidogrel is now more frequently used than ticlopidine due to better tolerability. In the CURE trial, clopidogrel was shown to lead to a 20% risk reduction for the composite endpoint of death from cardiovascular causes, nonfatal MI, or stroke (9.3% vs. 11.4%; risk ratio [RR], 0.80; 95% CI, 0.72-0.90; P < .001), but achieved at the cost of a higher bleeding risk (3.7% vs. 2.7%, RR, 1.38; 95% CI, 1.13-1.67; P = .001). However, there was no significant increase in life-threatening and fatal bleeds. In the CURE study, the efficacy of clopidogrel was consistent throughout all subgroups, irrespective of the initial risk. A trend toward an excess of bleeding was observed in patients submitted to CABG, in whom clopidogrel was withdrawn less than 5 days before surgery.
Recommendations for Oral Antiplatelet Drugs
Aspirin is recommended for all patients presenting with NSTE-ACS without contraindication at an initial loading dose of 160 to 325 mg (nonenteric) (I-A), and at a maintenance dose of 75 to 100 mg long-term (I-A).
For all patients, immediate 300-mg loading dose of clopidogrel is recommended, followed by 75 mg clopidogrel daily (I-A). Clopidogrel should be maintained for 12 months unless there is an excessive risk of bleeding (I-A).
For all patients with contraindication to aspirin, clopidogrel should be given instead (I-B).
In patients considered for an invasive procedure/PCI, a loading dose of 600 mg of clopidogrel may be used to achieve more rapid inhibition of platelet function (IIa-B).
In patients pretreated with clopidogrel who need to undergo CABG, surgery should be postponed for 5 days for clopidogrel withdrawal if clinically feasible (IIa-C).
Glycoprotein IIb/IIIa Receptor Inhibitors (GP IIb/IIIa Inhibitors)
Three GP IIb/IIIa inhibitors have been approved for clinical use, namely abciximab, eptifibatide, and tirofiban. They block the final common pathway of platelet activation by binding to the fibrinogen and, under high shear conditions, to the von Willebrand factor, and thus inhibiting the bridging between activated platelets. Abciximab is a monoclonal antibody fragment, eptifibatide is a cyclic peptide, and tirofiban a peptidomimetic inhibitor. Clinical studies with oral GP IIb/IIIa inhibitors were stopped because of an excess of ischemic events, an excess of bleeding, or both. The results obtained with the use of GP IIb/IIIa inhibitors differed according to whether their use was associated with a conservative or an invasive strategy.
Glycoprotein IIb/IIIa Receptor Inhibitors in a Conservative Strategy
A meta-analysis including 31,402 NSTE-ACS patients treated in clinical trials using GP IIb/IIIa inhibitors showed a 9% significant risk reduction for death and MI at 30 days (11.8% vs. 10.8%; OR, 0.91; 95% CI, 0.84-0.98; P = .015). GP IIb/IIIa inhibitors were associated with an increase in major bleeding complications. They were shown to be particularly effective in diabetics, patients with ST depression and troponin-positive patients.
Abciximab was tested in the GUSTO-4-ACS trial and did not show any superiority compared with the control group.
In the PURSUIT trial, which included 10,948 patients, eptifibatide led to a significant reduction of the 30-day composite endpoint of death or nonfatal MI (14.2 vs. 15.7%, eptifibatide vs. placebo; P = .04), but at the cost of an increase in the risk of TIMI major bleeding (10.6 vs. 9.1%; P = .02); however, there was no excess of intracranial bleeding.
Tirofiban has been tested in two trials. , In the PRISM trial, there was a significant risk reduction for the composite endpoint of death, MI, or refractory ischemia at 48 hours and 30 days, but this was not maintained in the long term. In the PRISM-PLUS trial, a significant reduction of the risk of death, MI, and refractory ischemia was obtained at 7 days (12.9% vs. 17.9%; RR, 0.68; 95% CI, 0.53-0.88; P = .004) and maintained at 30 days and 6 months in the tirofiban plus UFH group, as compared with UFH alone. Major bleeds (according to the TIMI criteria) were not statistically more frequent in the tirofiban group, despite a trend toward an increase (1.4% vs. 0.8%; P = .23).
Glycoprotein IIb/IIIa Receptor Inhibitors in an Invasive Strategy
Consistent results have been obtained in three different meta-analyses exploring the impact of the use of GP IIb/IIIa inhibitors in the setting of PCI. Two meta-analyses showed that a significant risk reduction for death and MI at 30 days could be achieved when GP IIb/IIIa inhibitors were administered before taking patients to the catheterization laboratory, and maintained during PCI. Kong and colleagues reported a significant risk reduction in 30 day mortality among a total of 20,186 patients (0.9% vs. 1.3%; OR, 0.73; 95% CI, 0.55-0.96; P = .024). Importantly, thienopyridines and stents were not routinely used in these trials.
The most recent trial with abciximab in this setting is ISAR-REACT 2, in which 2022 high-risk NSTE-ACS patients were randomized to dual antiplatelet therapy (aspirin or clopidogrel) or to triple antiplatelet therapy (abciximab in addition to aspirin and clopidogrel). The 30-day composite endpoint of death, MI, or urgent target vessel revascularization (TVR) occurred significantly less frequently in abciximab-treated patients versus placebo (8.9% vs. 11.9%; RR, 0.75; 95% CI, 0.58-0.97; P = .03). Triple antiplatelet therapy was efficacious only in troponin-positive patients.
Eptifibatide showed superiority over placebo in the ESPRIT trial. In this trial, a significant reduction in the risk of death, MI, urgent TVR, and bail-out use of GP IIb/IIIa inhibitors was demonstrated at 48 hours, and maintained at 30 days, and at 6 months (6.6% vs. 10.5%; RR, 0.63; 95% CI, 0.47-0.84; P = .0015 at 48 hours) for eptifibatide versus placebo.
In the TARGET study, tirofiban was shown to be inferior to abciximab possibly related to an inadequate dose. Newer, but smaller studies with higher bolus doses revealed a more potent antiplatelet effect.
Several trials have shown that LMWH, particularly enoxaparin, can be safely used with GP IIb/IIIa inhibitors, without compromising efficacy. It should be noted that most of the trials carried out with GP IIb/IIIa inhibitors were performed before clopidogrel was made available. However, ISAR-REACT 2 showed that triple antiplatelet therapy, associating aspirin, clopidogrel and abciximab, may lead to better outcome in high-risk NSTE-ACS patients submitted to PCI.
Bivalirudin and UFH/LMWH were shown to have equivalent safety and efficacy when used with triple antiplatelet therapy, including GP IIb/IIIa inhibitors in the ACUITY trial. However, bivalirudin alone was associated with a lower bleeding risk as compared with any combination with GP IIb/IIIa inhibitors.
Recommendations for Glycoprotein IIb/IIIa Inhibitors
In patients at intermediate to high risk, particularly patients with elevated troponins, ST-depression, or diabetes, either eptifibatide or tirofiban for initial early treatment are recommended in addition to oral antiplatelet agents (IIa-A).
The choice of combination of antiplatelet agents and anticoagulants should be made in relation to risk of ischemic and bleeding events (I-B).
Patients who received initial treatment with eptifibatide or tirofiban prior to angiography, should be maintained on the same drug during and after PCI (IIa-B).
In high-risk patients not pretreated with GP IIb/IIIa inhibitors and proceeding to PCI, abciximab is recommended immediately following angiography. (I-A) The use of eptifibatide or tirofiban in this setting is less well established (IIa-B).
GP IIb/IIIa inhibitors must be combined with an anticoagulant (I-A).
Bivalirudin may be used as an alternative to GP IIb/IIIa inhibitors plus UFH/LMWH (IIa-B).
When anatomy is known and PCI planned to be performed within 24 hours with GP IIb/IIIa inhibitors, most secure evidence is for abciximab (IIa-B).
Resistance to Antiplatelet Agents or Drug Interactions
Resistance to antiplatelet agents describes partial or total failure of an antiplatelet agent to achieve the expected inhibition of platelet function and would therefore be better named low- or hyporesponsiveness. The term refers to the variability in the magnitude of platelet aggregation inhibition measured ex vivo achieved in a population of treated patients. The magnitude of true resistance to antiplatelet agents remains poorly defined. No simple test has been reliably validated to assess the level of platelet function inhibition for any antiplatelet agent used in atherothrombosis. Resistance to antiplatelet agents was shown to lead to an increased risk of ischemic events. Drug interactions may also compromise the efficacy or safety of some drugs used in NSTE-ACS.
Resistance to aspirin has been identified in one substudy of the HOPE trial, in which different degrees of thromboxane A 2 inhibition were associated with a significant difference in rate of events. The variability in response observed with clopidogrel is probably linked to the variability in the two different steps of liver metabolism required to transform clopidogrel, which is a prodrug, into its active compound. There have been attempts to overcome this problem by raising the dose of clopidogrel. New ADP receptor antagonists are currently under clinical investigation.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to interact negatively with aspirin. A higher rate of events after NSTE-ACS has been observed in patients treated with NSAIDs. No formal interaction has been described with clopidogrel. However, the association of clopidogrel with vitamin K antagonists is not recommended, since it may potentially increase bleeding.
Recommendations for Resistance to Antiplatelet Treatment or Drug Interactions
Routine assessment of platelet aggregation inhibition in patients submitted to either aspirin or clopidogrel therapy, or both, is not recommended (IIb-C).
NSAID (selective COX 2 inhibitors and nonselective NSAIDs) should not be administered in combination with either aspirin or clopidogrel (III-C).
Clopidogrel can be administered with all statins (I-B).
The triple association of aspirin, clopidogrel, and VKA should only be given if compelling indication exists, in which case, the lowest efficacious INR and shortest duration for the triple association should be targeted (IIa-C).
Withdrawal of Antiplatelet Agents
Interruption of dual antiplatelet therapy soon after the acute phase of NSTE-ACS may expose patients to a high risk of recurrence of events, especially after stent implantation. If interruption of antiplatelet agents is necessary because of major bleeding or need for urgent surgery, for example, no alternative treatment can be proposed as a substitute. Temporary interruption of dual antiplatelet therapy is discouraged. Caution must be exercised when planning stent implantation. It is recommended to avoid drug-eluting stents in patients who may require urgent surgery in the short term.
Recommendations for Withdrawal of Antiplatelet Treatment
Temporary interruption of dual antiplatelet therapy (aspirin and clopidogrel) within the first 12 months after the initial episode is discouraged (I-C).
Temporary interruption for major or life-threatening bleeding or for surgical procedures where even minor bleeding may result in severe consequences (brain or spinal surgery) is mandatory (IIa-C).
Prolonged or permanent withdrawal of aspirin, clopidogrel or both is discouraged unless clinically indicated. Consideration should be given to the risk of recurrence of ischemic events which depends (among other factors), on initial risk, on presence and type of stent implanted, and on time window between proposed withdrawal and index event and/or revascularization (I-C).
Revascularization for NSTE-ACS is performed to relieve angina and ongoing myocardial ischemia, and to prevent progression to MI or death. The indications for myocardial revascularization and the preferred approach (PCI or CABG) depend on the extent and severity of the lesions as identified by coronary angiography, the patient’s condition, and comorbidity.
Invasive coronary angiography remains pivotal in determining suitability for percutaneous and/or surgical revascularization. In hemodynamically compromised patients (pulmonary edema, hypotension, severe life-threatening arrhythmias), it may be advisable to perform the examination after placement of an intra-aortic balloon pump, to limit the number of coronary injections and to omit left ventricular angiography.
Invasive Versus Conservative Strategy
Several meta-analyses have been performed on all trials that aimed to compare invasive versus conservative strategies in the setting of NSTE-ACS. With all the limitations linked to different definitions of endpoints, and due to the fact that many of the trials were not contemporary (no stents, no GP IIb/IIIa inhibitors, no clopidogrel), it has consistently been shown that invasive strategy followed by revascularization leads to an excess of events during the first month of evolution, but derives better long-term benefit in terms of risk reduction for death and death/MI. In addition, long-term follow-up of the FRISC-2 and RITA-3 trials confirmed that a significant improvement in outcome could be achieved with revascularization. , In this setting, the ICTUS trial failed to show a significant difference between invasive and conservative strategy. However, in this study, the rate of revascularization in the two arms was very similar.
It has not been consistently shown that very early intervention in patients with NSTE-ACS leads to better outcome, with the exception of the ISAR-COOL trial. As previously mentioned, early hazard may be associated with early intervention.
Accordingly, currently available evidence does not mandate a systematic approach of immediate angiography in NSTE-ACS patients stabilized with a contemporary pharmacologic approach. Likewise, a routine practice of immediate transfer of stabilized patients admitted in hospitals without on-site catheterization facilities is not mandatory, but should be organized within 72 hours.
Percutaneous Coronary Intervention (PCI)
Outcome after PCI in NSTE-ACS has been markedly improved with the use of intracoronary stenting and contemporary antithrombotic and antiplatelet therapy. The safety and efficacy of a drug-eluting stent (DES) has not been prospectively tested in this specific population, although patients with NSTE-ACS represent up to 50% of patients included in most PCI trials. In view of the potentially severe consequences of acute or subacute stent thrombosis, it is advisable to use a bare metal stent (BMS) in patients scheduled to undergo extracardiac interventions or surgery that will require interruption of clopidogrel within the first year after stent implantation. As long as the concerns about the long-term safety of DES have not been assuaged, and the situation completely clarified, the choice between use of BMS or DES should be based on an individual assessment of benefit versus potential risk.
Coronary Artery Bypass Graft (CABG)
The proportion of patients with NSTE-ACS undergoing bypass surgery during the initial hospitalization is about 10%. It is important to consider the risk of bleeding complications in patients who undergo bypass surgery while initially treated with aggressive antiplatelet treatment. Overall, pretreatment with triple or even dual antiplatelet regimen should be considered as only a relative contraindication to early bypass surgery but does require specific surgical measures to minimize bleeding and platelet transfusions. (See sections on GP IIb/IIIa inhibitors and Thrombocytopenia ).
Respective Indications for Percutaneous Coronary Intervention or Coronary Artery Bypass Graft
With the exception of an urgent procedure, the choice of revascularization technique in NSTE-ACS is the same as for elective revascularization procedures. From the randomized controlled trials comparing multivessel stented PCI with bypass surgery, there was no interaction between the presence of NSTE-ACS, treatment strategy, and outcome.
Recommendations for Invasive Evaluation and Revascularization
Urgent (<120 min) coronary angiography is recommended in patients with refractory or recurrent angina associated with dynamic ST deviation, heart failure, life-threatening arrhythmias, or hemodynamic instability (I-C).
Early (<72 hours) coronary angiography followed by revascularization (PCI or CABG) in patients with intermediate to high-risk features is recommended (I-A).
Routine invasive evaluation of patients without intermediate to high risk features is not recommended (III-C), but noninvasive assessment of inducible ischemia is advised (I-C).
PCI of nonsignificant lesions by angiography is not recommended (III-C).
After critical evaluation of the risk-to-benefit ratio, and depending on known comorbidities and potential need for noncardiac surgery in the short or medium term (e.g. planned intervention or other conditions) requiring temporary withdrawal of dual antiplatelet therapy, consideration should be given to the type of stent to be implanted (BMS or DES) (I-C).